Neoadjuvant FOLFOXIRI and Chemoradiotherapy Versus Neoadjuvant CAPOX/FOLFOX and Chemoradiotherapy Followed by Surgery or a Watch-and-Wait Approach in High Risk Locally Advanced Rectal Cancer

Summary

The aim of this clinical trial is to compare triplet induction therapy (FOLFOXIRI) with doublet induction therapy (CAPOX/FOLFOX), followed by chemoradiotherapy and either surgery or a watch-and-wait approach, in patients with high-risk locally advanced rectal cancer. The primary questions it seeks to address are whether triplet induction therapy results in higher complete response rates, improved quality of life, and better long-term oncological outcomes compared to doublet induction therapy, despite the anticipated increased risk of toxicity.

Conditions

• Locally Advanced Rectal Carcinoma

Interventions

DRUG

FOLFOXIRI

ICT consists of four or six two-weekly cycles of FOLFOXIRI. The dosages, dosage modification, and methods and schedule of administration of FOLFOXIRI follows the established treatment protocols and standard of care as prescribed in the Dutch Guidelines. It is administered as follows: * Day 1: irinotecan 165 mg/m2 body-surface area (BSA) intravenously (IV), followed by oxaliplatin 85mg/m2 BSA IV in combination with leucovorin 400mg/m2 BSA, followed by: * Day 1-2: 3200 mg/m2 BSA of continuous 5-fluorouracil IV * Day 3-14: rest days.

DRUG

CAPOX

The dosages, dosage modification, and methods and schedule of administration of CAPOX follows the established treatment protocols and standard of care as prescribed in the Dutch Guidelines. CAPOX is administered as follows: * Day 1: Oxaliplatin 130 mg/m2 body-surface area \[BSA\], intravenously \[IV\]. * Day 1-14: Capecitabine 1000 mg/m2 BSA, orally, twice daily. * Day 15-21: Rest days. This regimen is initially administered for three cycles. In case of responsive or stable disease, a 4th cycle of CAPOX will be administered. In case of unacceptable toxicity (physician's discretion) to oxaliplatin, CAPOX may be continued as FOLFOX.

DRUG

FOLFOX (5-fluorouracil, Leucovorin, Oxaliplatin)

FOLFOX is a combination chemotherapy regimen, consisting of: * 5-fluorouracil (chemical name: L01BC02; trade name: 5-Fluorouracil; formulation: concentrate for solution for injection) * Oxaliplatin (chemical name: L01XA03; trade name: Oxaliplatin Accord; formulation: concentrate for solution for injection) FOLFOX is a well-established chemotherapy combination regimen for colorectal cancer, and is authorised for its intended use in this study. All FOLFOX component agents will be sourced from commercially available hospital stock and prepared according to standard protocols at participating centres.

RADIATION

Chemoradiotherapy

In accordance with established standard-of-care protocols, chemoradiotherapy will commence 3-6 weeks after the completion of ICT, following restaging imaging and MDT review. The standard chemoradiotherapy regimen consists of external beam radiotherapy 50Gy in fractions of 2 Gy or 50.4 Gy in fractions of 1.8Gy combined with concomitant capecitabine, administered in accordance with Dutch Guidelines: * Dosage: 825 mg/m² Body Surface Area (BSA), twice daily * Route of administration: orally * Schedule: administered on all radiotherapy days * Treatment duration: 25 days In the case of cardiotoxicity or severe hand-foot syndrome due to capecitabine, treatment may be switched to Teysuno, in accordance with the Dutch guideline. The recommended dose of Teysuno in combination with oxaliplatin is 25 mg/m² body surface area, administered twice daily.

PROCEDURE

Total mesorectal excision (+/- IORT)

In patients with an incomplete response and resectable disease after first restaging, surgery is performed according to standard of care by a surgical oncologist with experience in rectal cancer surgery within 10-14 weeks after completion of chemoradiotherapy. The type and extent of the surgery is left to the discretion of the operating surgeon. In case of need for reconstructive surgery, the required specialist will be consulted and will attend the surgical procedure. The addition of IORT will be left to the discretion of the surgeon.

DIAGNOSTIC_TEST

Watch-and-wait approach

When a cCR is achieved after neoadjuvant therapy, patients may opt for a W\&W approach. A cCR is confirmed by imaging, endoscopy and digital rectal examination. Patients will receive a close surveillance follow up scheme according to the standard of care and local guidelines (51-54). Conduct follow-up every 3 months in the first year, every 6 months in the second year, and every 6 to 12 months in years 3 to 5, consisting of MRI and endoscopic evaluation. If any changes to the scar are detected during follow-up, a biopsy should be performed.

Sponsors & Collaborators

• ZonMw: The Netherlands Organisation for Health Research and Development

  collaborator OTHER

• J. W. A. Burger

  lead OTHER

Principal Investigators

• Jacobus WA Burger, Prof. dr. · Catharina Ziekenhuis Eindhoven

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-03-03

Primary Completion

2030-03-02

Completion

2034-03-02

Countries

• Netherlands

Study Locations